tbuckley/cabot-search huggingface dataset:
Integrated survival analysis.
Authors: Vi Kien Chiu, Adele Lerolle-Chiu
Journal: Journal of Clinical Oncology (2023)

e14695 Background: Clinical trial efficacy may be determined by the primary endpoint(s) of median progression free survival (mPFS) and/or median overall survival (mOS) from the Kaplan-Meier estimate, and secondary endpoints of overall response rate (ORR) and duration of response (DOR). In the treatment of metastatic cancers, single agent immunotherapy tends to have lower ORR and longer DOR in comparison to chemotherapy or targeted tyrosine kinase inhibitor therapy, which tends to have higher ORR and shorter DOR. This leads to intersecting or crossing Kaplan-Meier survival curves, which are harder to interpret. In immunotherapy trials, mPFS is a poor surrogate for mOS, and both may underrepresent the clinical benefit over time. Methods: We aimed to develop novel metrics that more effectively represent the Kaplan-Meier estimate. The graphical curve of the Kaplan-Meier estimate may be represented by the equation as a function of time. The integration of f ( x), which mathematically represents the area under the curve and clinically the cumulative or integrated survival benefit with time, is: ∫ 0 t f( x) dx = F(t) − F(0). Kaplan-Meier curve equation with constants C and A may be approximated by: ∫ 0 t C e -A x dx = C e -A t ]0 t = C( e -A t – 1). The average integrated clinical benefit with time is: 1/ t ∫ 0 t f( x) dx = [ F( t) − F(0)]/ t. Results: The Phase 3 KeyNote-061 trial of metastatic gastric cancer treated with single agent Pembrolizumab immunotherapy versus Paclitaxel chemotherapy was use for integrated PFS and iOS calculation. The Kaplan-Meier curves intersected or crossed in KeyNote-061 trial. We show the established ORR, mPFS, mOS, DOR. Integrated PFS (iPFS) and iOS were calculated with greater increase in iOS and much less decrease in iPFS for Pembrolizumab than Paclitaxel treatment. Conclusions: Integrated survival is a novel analysis that integrate the Kaplan Meier estimates and better represent the entire median survival and drug DOR may be combined into a single useful metric for overall clinical benefit. [Table: see text]
Comparative effectiveness trial of two supportive cancer care (SCC) delivery models at 24 clinics: An ongoing cluster randomized trial.
Authors: Hector S. Medrano, Emily H. Wood, Kris Kapphahn, Madhuri Agarwal, Cynthia C. Perez, Marika Matthew, Keely E. Fuller, Manali I. Patel
Journal: Journal of Clinical Oncology (2023)

e13617 Background: Many patients with cancer receive care that is misaligned with their goals, values and preferences and have undertreated symptoms. Proactive integration of advance care planning and symptom management -- Supportive Cancer Care (SCC) -- through team-based and technology-based approaches can overcome these deficiencies. Yet, it is unknown which approach is more effective. Methods: This 24-clinic cluster-randomized trial (NCT05297734) will evaluate whether a team-based SCC delivery approach using community health workers more effectively improves health-related quality of life (HrQOL) than a technology-based approach utilizing the electronic health record. We are enrolling 2996 patients across 24 clinics (12 randomized into each group) in the United States including integrated community clinics, academic, Kaiser, VA, and safety-net centers. Eligible patients are: ≥ 21 years; newly diagnosed with cancer; English or Spanish speakers. Those unable to consent, enrolled in competing trials, or planning to move within 12 months are excluded. The primary outcome is change in HrQOL using the Functional Assessment of Cancer Therapy-General survey from baseline to 3-months post-enrollment. Secondary outcomes include changes in patient activation, satisfaction, and healthcare use (emergency department visits, hospitalizations, chemotherapy, radiation, surgery, palliative care, hospice use) from baseline to 3-, 6-, and 12-months post-enrollment. Results: Enrollment began June 2022. As of December 2022, 24 clinics obtained IRB approval and 11 of 24 clinics screened a total of 1075 patients and enrolled a total of 165 participants. The majority (n=146; 77%) are male; 89 (53.9%) reported less than college degree; 45 (27.3%) reported annual household income ≤ $49,999. Conclusions: This ongoing study will inform the most effective SCC delivery approach and strategies to improve SCC across a variety of clinical settings in the United States. Clinical trial information: NCT05297734 . [Table: see text]
Use of PARPi among patients with HER2+ve MBC: Results from a real world dataset.
Authors: Shaheenah S. Dawood, Kaylen Brzozowski
Journal: Journal of Clinical Oncology (2023)

e13044 Background: Among individuals with germline mutations in BRCA1/ BRCA2 genes, life-time risk of developing breast cancer is approximately 50%. The majority of these cancers are HER2-ve with a low frequency of HER2+ve breast cancer (2.1%-10% in pts with BRCA1 mutations and 6.8%-13% of pts with BRCA2 mutations) with co-occurrence of BRCA mutation and HER2+ve status being a poor prognostic factor. PARPi have been shown in phase III trials to be effective in HER2-ve BRCA mutation MBC. The objective of this retrospective analysis was to look at the prognostic outcome associated with use of PARPi among pts with HER2 +ve BRCA mutated MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified patients with MBC who were treated with PARPi, and pts were assumed to have BRCA mutated MBC if they were recorded with a PARPi. Overall survival (OS) was computed using the Kaplan Meier product limit method. Pts with MBC were defined as having HER2+ve status if they received an anti-HER2 therapy after metastasis, HR+ve if they received endocrine therapy after metatstasis, and triple negative (TNBC) if they did not receive anti-HER2 therapy or endocrine therapy. Results: 1369pts with MBC were treated with PARPi, of whom 77.9%received olaparib. Mean age of pts was 57ys. 546(39.9%), 521(38.1%) and 73(5.3%) pts had TNBC, HR+ve/HER2-ve, and HER2+ve MBC, respectively. Among pts with HER2+ve disease, 35.2% and 74.0% had HR-ve and HR+ve MBC, respectively. Median time to use of PARPi was 7.1m, 15.1m, and 24.0m among pts with TNBC, HR+ve/HER2-ve, and HER2 +ve MBC respectively. Median OS was 44.4m, 47.0m, and 46.7m among pts with TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve disease, median OS was 74.5m and 31.5m among pts with HR+ve and HER-ve disease, respectively (HR=0.27, p=0.0001). 321(23.4%) pts had brain metastases of whom 36.8%, 36.4% and 8.1% had TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve MBC,38.3% received anti HER2 therapy before PARPi, 24.7% received anti HER2 therapy after PARPi and 37.0% received PARPi and anti HER2 therapy concurrently. Among pts with HER2+ve disease, median OS was 44.4m among those who received anti -HER2 therapy on or before PARPi and 93.8m among those who received anti-HER2 therapy after PARPi (HR 0.83, p=0.64).Among pts with brain metastases, median OS was 23.9m, 40.0m and 40.2m among pts with TNBC, HR+ve/HER-ve and HER2+ve MBC respectively. Conclusions: To our knowledge this is the first real world data set to report on the prognostic outcome of pts with HER2+ve BRCA mutated MBC. When PARPi inhibitors are given median OS is similar among the three subtypes of breast cancer. Although not significant, there appears to be a trend towards improved OS with earlier use of PARPi among patients with HER2+ve BRCA mutated MBC.
Comparing digital and glass slide methods for determining the HER2-low and negative categories in breast cancer.
Authors: Xuemin Xue, Changyuan Guo, Yun Ling, Rujing Jia, Wenting Huang, Yanfeng Xi, Jianming Ying
Journal: Journal of Clinical Oncology (2023)

e13042 Background: The promising clinical use of anti-HER2 antibody–drug conjugates (ADCs) in patients with immunohistochemistry (IHC)-based HER2-Low (1+, and 2+/FISH−) breast cancer has been discovered recently. Thus, pathologists and clinicians are now under increasing pressure to discriminate HER2-low from HER2-0. Methods: This multi-institutional retrospective breast cancer study selected 60 cases of paired digital and glass slides with HER2-Low (IHC 1+, and 2+/FISH−) and HER2-0 according to the original pathology reports, including 20 cases per staining intensity. These cases were re-evaluated by 37 pathologists from three hospitals. After excluding those cases with HER2 ≥ 2+ confirmed by both digital and glass slides with ≥ 85% agreement across 37 pathologists, the remaining cases were reclassified into “HER2-Neg” and “HER2-Low” categories with ≥ 85% agreement. If a slide could not be placed into one of these two categories, it will be labeled “HER2-Ambiguous”. Results: After excluding 13 cases with HER2 ≥ 2+ confirmed by both digital and glass slides with ≥ 85% agreement, the remaining 47 cases were reclassified into “HER2-Neg”, “HER2-Ambiguous” and “HER2-Low” categories. Therefore, the Kappa value for these three categories between the digital and glass slides was 0.597 (p = 2.50e-07). Interestingly, our study demonstrated that a significantly higher proportion of HER2-Low cases were identified on digital slides (48.9%, 23/47) than on glass slides (38.3%, 18/47; BhapkarTest, p = 3.17e-04). Five of the twelve (41.7%) HER2-Ambiguous cases diagnosed using glass slides were reclassified as HER2-Low using digital slides. Conclusions: Our study indicated that, compared to glass slides, digital slides may tend to shift HER2-0 to HER2-low category, potentially increasing breast cancer patients access to anti-HER2 ADCs, although the clinical benefit and biological characteristics have not been fully investigated. Thus, further investigation is warranted.
Development of allogenic nonviral RNA-based CAR-NK therapy targeting CDH17 in relapsed/refractory gastrointestinal cancer.
Authors: Jaydeep Roy, Vivian Lin, Mehran Rahmani, Kronos Chow, James Chieh-Liang Lin, Alarng Chang, John Moon Luk, Anthony Chun Fung Chan
Journal: Journal of Clinical Oncology (2023)

e14539 Background: Gastrointestinal (GI) cancers are commonly fatal after metastasis. The incidence and mortality of GI tumors are high, and the benefits of existing therapies are limited. Cadherin-17 (CDH17) is highly prevalent and specific to GI cancers which has potential for the development of novel treatments for GI cancers. Cell-based immunotherapy using genetically engineered autologous Chimeric Antigen Receptors T (CAR-T) cells has been clinically efficacious for treating hematological malignancies. However, its manufacturing is extremely expensive and lengthy with ~10% failure production rate. Equipping NK cells with CAR may represent a safer and equally effective approach for use in solid tumors as an alternative to autologous CAR-T-cell therapy. Nonviral RNA-based expression of CAR vector in NK cells will provide immediate and multiple accessibility to cancer patients, lower risk of abnormal genetic alteration mediated by viral integration, and potentially limit side effects. This paper demonstrates the development of RNA-CAR-NK targeting CDH17-positive GI cancers. Methods: Ex vivo expanded human peripheral blood NK (Magicell-NK, Medigen, Taiwan) cells were used in this study. To generate anti-CDH17 (C7) CAR-NK cells, mRNA containing a novel CDH17-specific single-chain variable fragment and the 4-1BB costimulatory domain was electroporated to Magicell-NK cell. Flow cytometry analysis was performed to evaluate the cell viability and the expression level of CAR and cytotoxic surface markers of the CAR-NK cells. CDH17 specific cytolytic activity against AGS gastric cancer cell line and the concentration of cytokines released by CAR-NK cells were measured by in vitro cytotoxicity assay and cytokine release assay, respectively. Results: Our results demonstrated efficient electroporation with high-level C7 CAR expression ( &gt; 80%) and optimal CAR-NK cell viability (~60%). Interestingly, 12 h co-culture of C7 CAR-NK cells with AGS gastric cancer cells at 1:1 and 2:1 effector/target (E:T) ratio showed a significantly enhanced antitumor response of C7 CAR-NK cells on AGS-CDH17+ cells but not on AGS-CDH17- cells, indicating CDH17 target-specific cytolytic activity. Moreover, we observed an elevated level of cytokines such as INF-γ and TNF-α released by C7 CAR-NK cells only in co-culture with AGS-CDH17+ cells, confirming the mechanisms behind the CAR-mediated cytotoxicity. Furthermore, these results were supported by an increased level of surface CD107a or LAMP-1 expression in C7 CAR-NK cells during the 12 h of co-culture with AGS-CDH17+ cells at 1:1 and 2:1 E:T ratio. Conclusions: Our findings suggest that a non-viral based CDH17 CAR-NK cell therapy could be a potential allogeneic, off-the-shelf CAR-NK therapy candidate in GI cancer and support the rationale of further investigating it in vivo and clinical trials.
Association of presenting symptoms with COVID-19 disease severity and outcomes among hospitalized patients with cancer and COVID-19.
Authors: Noman Ali, Ed Kheder, Kodwo Dickson, David Rubio, Kwame Koom-Dadzie, Paul Edelkamp, Heather Y. Lin, Mayoora Muthu, Alyssa Mohammed, Cerena Leung, Orhue Odaro, Michelle Sibille, Marina C. George, Josiah Halm, Joanna-Grace Mayo Manzano
Journal: Journal of Clinical Oncology (2023)

e13581 Background: COVID-19 has led to several waves of outbreaks over the last 2 years. Cancer patients are among the most vulnerable and have high morbidity and mortality rates. We aimed to determine the association between presenting symptoms and symptom burden and COVID hospitalization outcomes among cancer patients. Methods: We conducted a retrospective cohort study on all adult hospitalized cancer patients during their first admission at our cancer center from March 2020 to May 2021. We reviewed medical charts to identify reported symptoms. We used the Foundry data platform to compile and analyze data, including patient and hospitalization characteristics and outcomes. We used the chi-square test to test differences in categorical variables. Results: Our cohort included 595 patients, 272 with hematologic malignancies (45.7%) and 323 with solid tumor malignancies (54.3%). 52.1% were male, with an age range of 18 to 91 years (median age: 62). 64.2% self-identified as Caucasian, 16.1% as other, 14.3% as African American, and 3.5% as Asian. After univariate analysis, we found that female patients had higher rates of abdominal pain (21.4% vs. 14.5%, p=0.03), GI symptoms (36% vs. 27.4%, p=0.03), and sore throat (14.4% vs. 8.4%, p=0.02) than male patients. Smoking status or Charlson comorbidity score were not associated with any presenting symptoms. Solid tumor patients had higher rates of abdominal pain (26.6% vs. 7.4%, p &lt;0.01) than patients with hematologic malignancies. Patients with hematologic malignancies had higher rates of fever (59.2% vs. 42.7%, p&lt;0.01), cough (66.2% vs. 50.8%, p&lt;0.01), and shortness of breath (53% vs. 41.8%, p&lt;0.01) than solid tumor patients. Solid tumor patients more frequently reported more than 3 symptoms (52% vs. 39.2%, p&lt;0.01) than patients with hematologic malignancies. In terms of COVID outcomes, patients with cough (34.4% vs. 12%, p&lt;0.01), shortness of breath (38.5% vs. 12.9%, p &lt;0.01), and fever (29.1% vs. 20.6%, p=0.02) were more likely to have severe COVID-19. Patients with more than 3 symptoms were more likely to have severe COVID-19 (31.7% vs. 21.3% vs. 7.8%, p&lt; 0.01) than those with 1-3 symptoms or no symptoms. Patients with cough (15.1% vs. 6.4%, p&lt;0.01) and shortness of breath (15.5% vs. 7.9%, p&lt; 0.01) had higher inpatient mortality. Patients with chills (5.8% vs. 12.9%, p&lt; value 0.03) and headache (4.4% vs. 12.7%, p=0.02) had lower inpatient mortality. Conclusions: Our study showed that certain presenting COVID-19 symptoms are associated with patient and clinical characteristics, severity of disease, and inpatient mortality among adult hospitalized cancer patients.
Pyrotinib maleate for the treatment of brain metastases from HER2-positive solid tumours: A real-world study.
Authors: Qichao Wu, Kuanyu Wang, Shibin Sun, Xiaosheng Ding, Yichun Hua, Xiaoyan Li
Journal: Journal of Clinical Oncology (2023)

e13041 Background: Pyrotinib maleate is a small molecule, irreversible inhibitor of HER1, HER2 and HER4 tyrosine kinases developed in China. A number of clinical studies have confirmed the good efficacy in treating patients with HER2-positive solid tumours and HER2-positive breast cancer brain metastases. In this study, we ulteriorly explore the curative effect and safety of pyrotinib in HER2-positive solid tumours brain metastases treatment. Methods: Clinical data from 53 patients with HER2-positive solid tumor brain metastases enrolled were compiled and analyzed. The impact of whether pyrrolizidine was combined with chemotherapy, a large molecule TKI, and intracranial local radiotherapy on PFS and intracranial PFS in the enrolled patients is somewhat outlined. Results: From June 2021 to December 2022, according to 53 patients with HER2-positive solid tumor brain metastases availably measured intracranial metastases meeting RECIST 1.1 criteria at baseline, with the dosing regimen based on pyrotinib and the combination or intracranial radiation therapy following the clinician's choice. The recorded patients included 49 patients with breast cancer, 2 patients with lung adenocarcinoma, and 1 patient with gastric cancer. A total of 37 patients were HER2-positive by immunohistochemistry, 4 patients were HER-positive by genetic testing, 9 patients were HER2-positive by fluorescence in situ hybridization, and the remaining 3 patients had unknown HER2 status. A total of 27 patients had one or more radiation treatments for intracranial metastases, 39 patients with treatment regimens combining chemotherapy with pyrotinib, and 19 patients with combination of large molecule TKI. The selected 53 patients base in the study, had disease progression due to new intracranial metastases or enlarged intracranial metastases in 42. The mPFS was 12 months for all patients and 13 months for intracranial metastases. Further collated analysis has shown there was no significant difference in mPFS between subgroups according to age, method of HER2 detection, lines of therapy, whether or not combined with chemotherapy, and possibility of combining with large molecule TKI therapy. There was a remarkable difference in PFS between the combined intracranial radiation therapy group and the non-combined intracranial radiation therapy group (14.6 months vs. 11.4 months, p = 0.042). There was also a significant variance in intracranial PFS between the combined intracranial radiation treatment group and the non-combined intracranial radiation treatment group (15.8 months vs. 12.0 months, p = 0.023). Conclusions: Pivotally, pyrotinib has shown good clinical efficacy in patients with HER2-positive solid tumor brain metastases. The results of this study suggest that early intervention with intracranial local radiation therapy is utterly essential for HER2-positive patients with brain metastases at baseline.
Disparate impact of healthcare access restrictions due to COVID-19 pandemic on breast cancer diagnosis and treatment.
Authors: Devi Nair, Rakhshanda Layeequr Rahman, Karla Daniele, Brooke Jensen, Chathurika S. Dhanasekara
Journal: Journal of Clinical Oncology (2023)

e13518 Background: The COVID-19 pandemic altered healthcare access avenues for patients. In May 2020, 79% of cancer patients in the US in active treatment experienced some delay in their healthcare due to COVID-19 related restrictions. Hispanic patients are known to be disproportionately affected by their social determinants of health, and therefore are at higher risk of being affected by the pandemic. Our institution, designated as a “Hispanic Serving Institute (HSI)”, is ideally suited to study the impact of the pandemic on this population. Methods: In this retrospective study, the institutional breast cancer database was queried for patients managed between January 1, 2018 and April 18, 2022. Socio-demographic variables, screening, and treatment initiation dates were analyzed to determine the impact of COVID-19 related restrictions. Patients were stratified into groups based on date of diagnosis: Group 1 (pre-pandemic), Group 2 (pandemic), and Group 3 (post pandemic). Statistical analyses were conducted using R statistical software (R version 4.1.3). ANOVA or Kruskal Wallis tests with multiple pairwise comparisons using independent samples t-test or Wilcoxon rank sum test and χ2 tests with multiple pairwise comparisons using Fisher’s exact test were used to compare the groups. Interaction models were created to evaluate the association between 1) Ethnicity and 2) Distance from the treatment center on the time lapses between 1) mammogram and biopsy and 2) biopsy and first treatment separately. Results: Of the 488 patients during study period, 163 (33%) patients were Hispanic. Median (IQR) number of days between biopsy and first treatment was similar across all groups [Group 1=39.5 (102.5) days; Group 2= 50 (121) days; Group 3=57 (54) days - p=0.338]. Patients who lived &gt; 50 miles away from the treatment facility experienced longer time lapses between biopsy date and first treatment compared to those living ≤ 50 miles away (β= 40.60, SE (standard error) =20.87, p = 0.052). Compared to Non-Hispanics, Hispanics in Group 2 experienced a shorter time lapse between mammogram and biopsy (β= -17.34, SE=5.46, p = 0.002). However, these patients experienced a longer time lapse between biopsy and initiation of treatment (β= 43.57, SE=18.25, p = 0.017). There was a significantly higher proportion of non-insured patients in the Hispanic group compared to the non-Hispanic group [Hispanic group=12 (7.4%) patients; Non-Hispanic group=8 (2.5%) patients - p=0.020]. Conclusions: Pandemic related delays in breast cancer treatment were observed mainly in Hispanics and patients living more than 50 miles from the treatment center.